In prior art it is well known that when the pH of a protein comprising DOPA residues is raised above about 5, auto oxidation of DOPA to dopaquinone is achieved. It is well known that this auto oxidation is faster with a higher pH.
In adhesive compositions intended for biological tissue it is not suitable to have very high or very low pH. From a perspective of sensitive tissues a pH value of about 5.5 to 7.5 is often suitable. It was always anticipated that such a low pH give too slow curing of the adhesive. Previous strategies to increase the speed of the adhesion have been to raise pH, as disclosed in WO 2003/051418, to lower the pH and use a concentrated solution as disclosed in WO 2004/005421, or add periodate ions as disclosed in WO 2003/080137.
WO 2003/051418 discloses method for attaching two surfaces or for coating a surface comprising the steps of a) providing a bioadhesive composition consisting of an aqueous solution of a bioadhesive polyphenolic protein derived from a byssus-forming mussel, which protein comprises 30-300 amino acids and consists essentially of tandemly linked peptide repeats comprising 3-15 amino acid residues, wherein at least 3% and preferably 6-30% of the amino acid residues of said protein are DOPA, wherein the concentration of said protein in said bioadhesive composition is within the range of 10-50 mg/ml; b) providing a strongly alkaline solution with a pH of 10 or more; c) (i) mixing said composition and said strongly alkaline solution and applying the mixture to at least one of two surfaces to be attached to each other or (ii) applying said composition and said strongly alkaline solution sequentially, without any specific order, to at least one of two surfaces to be attached to each other, thereby mixing the bioadhesive composition and the strongly alkaline solution; d) optionally joining said surfaces to each other; and e) leaving said surfaces for sufficiently long time for curing to occur. There is also disclosed a corresponding kit.
WO 2003/051418 further discloses mostly when using the polyphenolic proteins as adhesives the pH has had to be raised to neutral or slightly basic (commonly to from 5.5 to 7.5) in order to facilitate oxidation and curing of the protein. However it is added that curing is slow and results in poor adhesive strength. It is also taught that addition of oxidizers, fillers cross-linking agents often is necessary. The selected pH is from a perspective of adhesives to be used for tissues.
WO 2004/005421 discloses use of a composition as a sole component for attaching two surfaces to each other or for coating a surface, said composition consisting of an acidic aqueous solution of a bioadhesive polyphenolic protein derived from a byssus-forming mussel, which protein comprises 30-300 amino acids and that consists essentially of tandemly linked peptide repeats comprising 3-15 amino acid residues, wherein at least 3% and preferably 6-30% of the amino acid residues of said protein are DOPA, where the pH of said acidic solution is 4 or less, and wherein the concentration said protein is 10-250 mg/ml.
WO 2003/080137 discloses a method for attaching two surfaces or for coating a surface comprising the steps of a) providing a bioadhesive composition consisting of an aqueous solution of a bioadhesive polyphenolic protein, which protein comprises 30-300 amino acids and consists essentially of tandemly linked peptide repeats comprising 3-15 amino acid residues, wherein at least 3% and preferably 6-30% of the amino acid residues of said protein are DOPA; b) providing a preparation comprising periodate ions; c) mixing said bioadhesive composition and preparation comprising periodate ions so that the periodate ions constitutes at least 1.80 mmol/g of the final composition; d) (i) applying the mixture to at least one of two surfaces to be attached to each other or (ii) applying said composition and said preparation comprising periodate ions without any specific order, to at least one of two surfaces to be attached to each other, thereby mixing the bioadhesive composition and preparation comprising periodate ions; e) optionally joining said surfaces to each other; and f) leaving said surfaces for sufficiently long time for curing to occur.
Although the strategies used in the prior art give cured compositions there is room for improvement regarding the adhesive. For instance the strength of the adhesive may be improved.
Another problem in the prior art is how to provide an improved adhesive which can be dried, stored and used after a period of storage.
Yet another problem is how to provide a tissue friendly adhesive.